Chemotherapeutic Drugs
Wei-Ping Zhang, PhD
张纬萍
Dept. of Pharmacology,
School of Medicine, Zhejiang University
weiping601@zju.edu.cn
2013.12.16
Chapter 34
General Considerations
for chemotherapeutic drugs
Overview
I. Chemotherapy
II. Chemotherapeutic agents
III. Mechanisms under the action of
chemotherapeutic agents
IV. Bacterial Resistance
V. Basic principle of clinical usage of
antimicrobial agents
I. Chemotherapy
Louis Pasteur 1822-1895
The Birth of Modern
Chemotherapy: Dreams
of a “Magic Bullet”
Robert Koch 1843-1910
Rebecca Lancefield 1896-1981
I. Chemotherapy
Paul Ehrlich introduced an arsenic-containing chemical
called salvarsan （阿斯凡纳明）to treat syphilis （梅毒）
(1910).
–“Magic bullet” for treatment of syphilis
1928 Fleming discovers penicillin
I. Chemotherapy
History of Antimicrobial Therapy
1928
I. Chemotherapy
History of Antimicrobial Therapy
• 1928 Fleming discovers penicillin (青霉素)
• 1932 Domagk discovers sulfonamides （磺胺类）
• 1940s Penicillin and streptomycin （链霉素） used widely,
cephalosporins （头孢霉素） discovered
• 1947 Chloramphenicol （氯霉素）discovered, first broad spectrum
agent
• 1950s Tetracycline（四环素） in use
• 1952 Erythromycin（红霉素） discovered (macrolides，大环内脂类)
• 1956 Vancomycin（万古霉素） used for penicillin-resistant S.
aureus
• 1957 Kanamycin（卡那霉素） discovered (aminoglycosides，氨基
糖苷类)
• 1962 Nalidixic acid（奈啶酸） discovered (quinolones，喹诺酮类)
• 1980s Fluoroquinolones（氟喹诺酮）, broad spectrum
cephalosporins（广谱头孢类）
• 2000s Newer agents to combat resistant pathogens
I. Chemotherapy
History of Antimicrobial Therapy
Endless way ………………
MRSA，NAM-1
Superbug……drug resistance
II. Chemotherapeutic agents
II. Chemotherapeutic agents
Host Factors：
patient’s age,
gender,
constitution,
hepatic, renal
function
pathogenicity
Immunological
responses
II. Chemotherapeutic agents
 Antimicrobial drugs
Antibacterial drugs
Antifungal drugs
Antiviral drugs
 Antiparasitic durgs
 Antineoplastic / anticancer drugs
II. Chemotherapeutic agents
Ideal antimicrobial drugs
 High sensitivity
 Nontoxic or low-toxic (safety)
 Nonresistance
 Satisfied pharmacokinetic
properties
 Good price
II. Chemotherapeutic agents
Antibacterial drugs (抗菌药)
 kill bacteria and arresting its growth
 antibiotics and synthetic
antimicrobial agents such as
sulfonamides(磺胺类) and
quinolones (喹诺酮类).
II. Chemotherapeutic agents
Antibiotics（抗生素）
Produced by various species of
microorganisms (bacteria, fungi ,
actinomycetes) and semi-synthetic
Suppress the growth of other
microorganisms.
II. Chemotherapeutic agents
Antibacterial spectrum（抗菌谱）
• Narrow?
• Broad?
Chemotherapetic index (CI)（化疗指数）
• CI= LD50 / ED50
• CI= LD5 / ED95
II. Chemotherapeutic agents
药理作用
中毒作用
TD50
ED95
LD5
致死作用
II. Chemotherapeutic agents
Bacteriostatic drugs （抑菌药）
inhibit the growth of microorganisms
e.g. Sulfonamides, Tetracycline
Bactericidal drugs （杀菌药）
• kill microorganisms
e.g. Penicillin, Aminoglycosides
II. Chemotherapeutic agents
Bactericidal vs Bacterostatic
II. Chemotherapeutic agents
Minimum inhibitory concentration (MIC)
最低抑菌浓度
Minimum bactericidal concentration (MBC)
最低杀菌浓度
Post antibiotic effect (PAE)
抗生素后效应
Resistance （耐药性）
Cross Resistance （交叉耐药性）
First expose effect （首次接触效应）
II. Chemotherapeutic agents
最低抑菌浓度
最低杀菌浓度
最低抑菌浓度
最低杀菌浓度
II. Chemotherapeutic agents
Incubate 18 to
24 hr at 37℃
Measure
diameters of
nongrowth
zones
Disk diffusion method for testing bacteria for susceptibility to specific antimicrobial drugs.
III. Mechanism of action
III. Mechanism of action
1. Inhibit synthesis of bacterial cell walls
2. Affecting permeability of cell membrane
and leading to leakage of intracellular
compounds
3. Inhibit protein synthesis
4. Affect bacterial nucleic acid metabolism
5. Block essential enzymes of folate
metabolism
III. Mechanism of action
1. Inhibiting synthesis of bacterial cell walls
e.g. penicillins, b-lactams
III. Mechanism of action
UDP-乙酰葡萄糖胺
乙酰胞壁酸-5肽
III. Mechanism of action
2. Affecting permeability of membrane
 Ionic- sorbent （离子吸附剂）
e.g. Aminoglycosides （氨基糖苷类）
 Binding to ergosterol （麦角固醇）
e.g. Nystatin (制霉菌素)
Amphotericin B（两性霉素）
 Cationic detergent
e.g. polymyxins（多粘菌素）
III. Mechanism of action
2. Affecting permeability of membrane
Lipopoly
-saccharide
Outer
membrane
Peptidoglycan
Cytoplasmic
membrane
polymyxins
III. Mechanism of action
3. Inhibiting protein synthesis
Ribosomal structure
• Bacteria 30S + 50S
70S
30S subunit
• binds mRNA in initiation complex
• holds growing peptide chain
50S subunit
accepts / translocates charged tRNAs
• "A" site --> Aminoacyl-tRNA (acceptor) site
• "P" site --> Peptidyl-tRNA (donor) site
• Mammals 40S + 60S
80S
III. Mechanism of action
3. Inhibiting protein synthesis
P
A
III. Mechanism of action
3. Inhibiting protein synthesis
大环内酯类
氨基糖苷类
P
四环素
氯霉素
林可霉素
A
氨基糖苷类
III. Mechanism of action
4. Affecting bacterial nucleic acid metabolism
(+)
Break back
segment
(-)
(-)


Rifampicin (利福平): inhibit DNAdependent RNA polymerase
Ridarabine (阿糖腺苷), Ganciclovir
(更昔洛韦) inhibit DAN polymerase
III. Mechanism of action
5. block essential enzymes of folate metabolism
蝶啶
Pteridine + PABA
Dihydropteroate
synthase
二氢蝶酸
对氨基苯甲酸
Blocked by
sulfonamides
Dihydropteroic acid
glutamate
Dihydrofolic acid
Dihydrofolate
reductasease
NADPH
Blocked by trimethoprim
NADPH
Tetrahydrofolic acid
甲氧苄啶
IV. Bacterial Resistance
 Intrinsic resistance
– Inherent features ，usually expressed by
chromosomal genes
 Acquired resistance
– Emerge from previously sensitive bacterial
populations
– Caused by mutations in chromosomal
genes
– Or by acquisition of plasmids or
transposons
IV. Bacterial Resistance
IV. Bacterial Resistance
Bacterial Resistance- Mechanisms
• The drug is not active.
• The target is altered.
• The drug does not reach its target.
IV. Bacterial Resistance
1.The drug is not active.
 Production of aminoglycoside-modifying
enzymes and β-lactamase;
IV. Bacterial Resistance
2.The target is altered
Mutation of the natural
target (quinolone
resistance)
Substitution with a
resistant alternative to the
native, susceptible target
(methicillin（甲氧西林）
resistance)
IV. Bacterial Resistance
2.The target is altered
Target modification
(ribosomal protection
type of resistance to
macrolides and
tetracyclines)
IV. Bacterial Resistance
3.The drug does not reach its target
Absence, mutation or
loss of the appropriate
transporter or porins
(膜孔蛋白）
IV. Bacterial Resistance
3.The drug does not reach its target
Active efflux system (主
动排出系统)
 Efflux transporter
（转运子）
 Accessory protein
（附加蛋白）
 Outer membrane
channel（外膜蛋白）
IV. Bacterial Resistance
Active efflux system（主动排出系统 ）
Outer membrane
channel
transporter
Accessory protein
IV. Bacterial Resistance
Laura J. V. Piddock
Nature Reviews Microbiology 4, 629-636 (August 2006)
IV. Bacterial Resistance
The transfer of Resistance genes
 From human  human
 From bacteria  bacteria
 Intracellular
 Mutations 突变
 Transduction 转导
 Transformation 转化
 Conjugation 接合
IV. Bacterial Resistance
Mutations 突变
IV. Bacterial Resistance
Mutations 突变
May occur in the gene encoding
 The target protein
 A protein involved in drug transport
 A protein important for drug activation
 A regulatory gene or promoter affecting
expression of the target, a transport protein,
or an inactivating enzyme
IV. Bacterial Resistance
Transduction 转导
IV. Bacterial Resistance
•Transformation 转化
•Conjugation 接合
IV. Bacterial Resistance
IV. Bacterial Resistance
Multi-drug resistance
(MDR)
1. Methicillin-resistant staphylococcus
aureus, MRSA
甲氧西林耐药金黄色葡萄球菌
Methicillin-resistant coagulase
negative staphylococci, MRCNS
甲氧西林凝固酶阴性葡萄球菌
PBP-2a （a 78kD new PBP）
IV. Bacterial Resistance
Multi-drug resistance MDR
2. Penicillin-resistant streptococcus pneumoniae,
PRSP，青霉素耐药肺炎链球菌
•
PBP-1a, PBP-2a, PBP-2x, PBP-2b （78-100 kD）
•
Active efflux system （express mef(A)对大环内酯
类）
3. Vancomycin-resistant Enterococcus, VRE
万古霉素耐药肠球菌
•
PBP avidity ↓
•
van-A, van-B, van C-1, van C-2, van D, van E
IV. Bacterial Resistance
Multi-drug resistance MDR
4. The 3rd generation-cephalosporins -resistant
• Extended spectrumβ-lactamases, ESBL
超广谱β- 内酰胺酶
• Class I chromosone mediated β-lactamases
I类染色体介导的β- 内酰胺酶
• E.g. 大肠埃希菌、克雷伯肺炎杆菌、阴沟肠杆菌
IV. Bacterial Resistance
Multi-drug resistance MDR
5. Carbapenem (碳青霉烯) –resistant：对亚胺培
南的铜绿假单胞菌敏感
• OprD porin
• Metalβ-lactamases （金属β- 内酰胺酶 ）
6. Quinolone-resistant escherichia coli（大肠
埃希菌）, AREC
• Active efflux system
• Cross-resistance
superbug or super bacterium
Basic principle of clinical usage of antimicrobial agents
Antimicrobial drugs -Characteristics
Some laboratory techniques that are
useful in the diagnosis of microbial
diseases
Basic principle of clinical usage of antimicrobial agents
Antimicrobial drugs -Characteristics
According to bio-activity






Anti G+ antibiotic
Anti G- antibiotic
Broad-spectrum antibiotic
Anti mycobacterium antibiotic
Anti anaerobe antibiotic
b- lactamase inhibitor
Basic principle of clinical usage of antimicrobial agents
Antimicrobial drugs -Characteristics
According to the chemical structure：
1. b-lactams (b-内酰胺类）；Penicillins（青霉素
类）；Cephalosporins（头孢菌素类）;
2. Aminoglycosides(氨基糖苷类);
3. Macrolides （ 大 环 内 酯 类 ） ; Lincosamides
（林可胺类）;Vancomycins（万古霉素类）
4. Tetracyclines（四环素类）；
Chloramphenicol (氯霉素)
Basic principle of clinical usage of antimicrobial agents
5. Quinolones (喹诺酮类 )
6. Sulphonamides (磺胺类 )
7. Nitrofurans (硝基呋喃类)
8. Antimycobacterial agents (抗结核分
支杆菌类 )
9. others:
Oxazolidinones（恶唑烷酮类）
Streptogramins（链阳菌素类）
Basic principle of clinical usage of antimicrobial agents
Some clinical situation in which prophylactic antibiotics
Basic principle of clinical usage of antimicrobial agents
Some clinical situation in which prophylactic antibiotics
Basic principle of clinical usage of antimicrobial agents
防止抗菌药物的不合理应用的注意点：
1）抗菌药物对病毒无治疗作用，除非伴有细菌感染或
继发感染，一般病毒感染不应该使用抗菌药物；
2）原因未明的发热者，除非伴有感染，一般不使用抗
菌药物治疗；
3）应尽量避免抗菌药物的局部应用，否则可引起细菌
耐药和变态反应；
4）使用抗菌药物剂量要适宜，疗程要足够。
Summary
I. Chemotherapy
II. Chemotherapeutic agents
terminology
III. Mechanisms under the action of
chemotherapeutic agents
 Inhibiting synthesis of bacterial cell walls
 Affecting permeability of membrane
 Inhibiting protein synthesis
 Affecting bacterial nucleic acid metabolism
 Block essential enzymes of folate metabolism
IV. Bacterial Resistance
 Intrinsic resistance
– Inherent features ，usually expressed by
chromosomal genes
 Acquired resistance
– Emerge from previously sensitive bacterial
populations
– Caused by mutations in chromosomal
genes
– Or by acquisition of plasmids or
transposons
V. Basic principle of clinical usage of antimicrobial
agents